Stepped treatment algorithm using budesonide-formoterol for chronic respiratory diseases: A single arm interventional study

Background While the safety and efficacy of inhaled budesonide-formoterol, used as-needed for symptoms, has been established for patients with asthma, it has not been trialed in undifferentiated patients with chronic respiratory diseases. We aimed to assess the feasibility of a pragmatic intervention that entails a stepped algorithm using inhaled budesonide-formoterol (dry powder inhaler, 160μg/4.5μg per dose) for patients presenting with chronic respiratory diseases to three rural district hospitals in Hanoi, Vietnam. Methods We recruited patients with evidence of airflow obstruction on spirometry and/or symptoms consistent with asthma. The algorithm consisted of three steps: 1. as-needed inhaled budesonide-formoterol for symptoms, 2. maintenance plus as-needed inhaled budesonide-formoterol, and 3. referral to a higher-level healthcare facility. All participants started at step 1, with escalation to the next step at review visits if there had been exacerbation(s) or inadequate symptom control. Patients were followed for 12 months. Results Among 313 participants who started the treatment algorithm, 47.2% had ≥ 1 episode of acute respiratory symptoms requiring a visit to hospital or clinic and 35.4% were diagnosed with an exacerbation. Twelve months after enrolment, 50.7% still adhered to inhaled budesonide-formoterol at the recommended treatment step. The mean and median number of doses per day was 1.5 (standard deviation 1.2) doses and 1.3 (interquartile range 0.7–2.3) doses, respectively. The proportion of patients taking more than 800μg budesonide per day was 3.8%. Conclusion This novel therapeutic algorithm is feasible for patients with chronic respiratory diseases in a rural setting in Vietnam. Further studies are required to establish the effectiveness, safety and cost-effectiveness of similar approaches in different settings. Trial registration ACTRN12619000554167.

o Oversee data collection and entry, ensuring that data is entered electronically in an accurate and timely way. o Maintain the equipment for the study, and ensure it is properly accounted for according to institutional policies.

Position description: Project Officer (Research student)
The Project Officer (Research student) will fulfill the following roles:

Position description: District Coordinator
In each District Clinic, a District Coordinator will be appointed to oversee the study locally. This person will be responsible for the following: o If a current smoker themselves, and they agree to participate, the health workers will be invited to participate in a health worker smoking cessation program

BACKGROUND AND RATIONALE
Chronic respiratory disease (CRD), one of the four major noncommunicable diseases worldwide, consists of a variety of diseases such as chronic obstructive pulmonary disease (COPD) and asthma. COPD is predicted to become the third biggest cause of death by 2030. Asthma is also one of the most important causes of disability worldwide. Both conditions are characterized by chronic airway inflammation and exacerbations that are recognised by sudden worsening of pulmonary function and respiratory symptoms. They also share risk factors, such as smoking, air pollution and respiratory infections.
In Vietnam, both COPD and asthma are common health issues that pose significant burden to the health system. COPD was estimated to affect 7.1% of adult in a northern population 1 . The prevalence of asthma was shown to be 5.6% in adult and 13.9% in school children 2,3 . Based on a review on noncommunicable disease by Vietnam Ministry of Health, COPD and asthma account for more than 7% of total disability adjusted life years across the country 4 .
Evidence from previous studies have demonstrated cost-effective interventions to prevent and reduce the burden of CRD. Interventions on tobacco control are also effective in reducing symptoms, preventing disease deterioration and exacerbations.
However, despite available evidence-based international guidelines and cost-effective interventions, barriers lie in between those approaches and vulnerable populations, particularly in resource-limited settings 5-7 . Challenges are there to implement optimal care in Vietnam. Recent surveys in Vietnam showed low percentage of asthma guideline adherence among primary care physicians and insufficient awareness of hospital doctors toward COPD management 8,9 . Among patients with COPD, less than 10% received any form of inhaled medications and 24% had required an unplanned health care visit. The availability and affordability of effective treatment are also a barrier that may hinder proper patient management 10,11 . Furthermore, national policy to reduce tobacco smoking, one major risk factor of CRD, has not yet been successful, with 45% of males still smoking in 2015 12 . The gap between evidence-based practice and current disease management requires further investigation to address the burden of CRD.
In light of this, two baseline surveys, which kick off the Vietnam COPD, Asthma and VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version 8 Prevention of Smoking (VCAPS) study, are currently underway to elucidate the current context and barriers to optimal care. The VCAPS 1 will contribute to an understanding of respiratory disease and smoking practices among patients presenting to health facilities. The current practices and attitudes regarding disease management and tobacco control will be characterised in the VCAPS 2 study.
The present study (VCAPS 3) will serve as a pilot study for a randomised controlled trial (VCAPS 4, a cluster RCT) that aims to show the effectiveness of an integrated public health intervention to reduce the number of exacerbations among patients with symptomatic CRD. The results of the two surveys and this pilot study will inform the design of the VCAPS 4 RCT.
VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version

OBJECTIVES
The project proposed in this document (VCAPS 3) is a prospective cohort study that will inform the design of the VCAPS RCT (the VCAPS 4 RCT). The aim of the VCAPS 4 RCT will be to demonstrate the effectiveness of an integrated public sector intervention to reduce the number of exacerbations among individuals with CRD presenting to healthcare facilities. The specific objectives of the VCAPS 3 study (the present study) are as the following. Steps in the cascade will include:

Chronic respiratory diseaseobjectives
• The proportion of patients attending a health facility presenting with chronic respiratory symptoms consistent with CRD.
• The proportion of patients with chronic respiratory symptoms who initiate diagnostic assessment • The proportion of patients who complete spirometry / peak expiratory flow.
• The proportion of patients completing diagnostic assessment who are diagnosed with CRD.
• The proportion of patients with CRD who commence treatment with ICS/LABA therapy, according to the study algorithm.

OVERVIEW OF STUDY DESIGN
This is a prospective cohort study aims to assess the feasibility of an integrated public sector intervention that is hypothesised to (a) reduce the number of exacerbations among individuals with CRD presenting to healthcare facilities and (b) reduce the proportion of current smokers among patients presenting to healthcare facilities and HCWs in the facilities.
Three interventions will be implemented, including (a) chronic respiratory disease intervention, (b) patient smoking cessation intervention, and (c) health facility smoking cessation intervention. Patients with CRD, diagnosed by the demonstration of airflow limitation or a respiratory symptom questionnaire, will be recruited to the chronic respiratory disease intervention. Patients who are current smokers will be invited to join the patient smoking cessation intervention. The health facility smoking cessation intervention is a facility-wide program that will implement a 'smoke free hospital' approach, including smoking cessation advice and facility-wide interventions to mitigate smoking among patients and staff in the selected district facilities. Training will be provided to HCWs in the three district facilities before participant recruitment.
The recruitment period for both components of the study will be 16 weeks. The follow-up period will be 12 months.

Co-primary outcomes
Co-primary outcomes of the study are: Definitions for each of these terms are included in the glossary.
The overview of the study is shown in Figure 1.

DETAILED PROCEDURES OF THE STUDY Study design:
This is a prospective cohort study.

Settings
This study will be conducted in three government district health facilities in rural districts of Hanoi Capital.

Study population
The study population is patients presenting consecutively to selected district facilities and HCWs in the facilities. Specifically, patients who present to selected district facilities with chronic respiratory symptoms are considered eligible for the chronic respiratory disease intervention. Patients visiting the facilities who are current smokers are eligible for patient smoking cessation intervention. Health facility smoking cessation intervention will be a facility-wide intervention in which smoking employees of the facilities are invited for the SCP.

Inclusion criteria for chronic respiratory disease intervention
(a) Patients aged 12 years and over presenting to district health facilities, AND (b) At least one of cough, dyspnea, wheeze, or chest tightness, AND (c) A history of at least one prior episode of respiratory symptoms that has required attendance at a public or private health care facility or private pharmacy within the past two years, AND (d) Demonstrated airflow limitation, defined as a pre-bronchodilator FEV1/FVC ratio less than 70% on spirometry or a peak flow meter reading less than 80% of predicted peak expiratory flow rate. Spirometry is the preferred method. Patients who cannot achieve acceptable spirometry result 13 will perform peak expiratory flow instead as performing peak expiratory flow is less complicated and safer than spirometry. The contraindications are listed in Table 1. OR (e) Probable asthma: answering yes to at least three of the nine questions in the respiratory symptom questionnaire ( Table 2). The questionnaire is adopted from a previously validated questionnaire 14 .
VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version (f) An alternative diagnosis, other than obstructive airway disease, is unlikely to explain the respiratory symptoms. Common alternative diagnoses and their features are listed in Table 3.
(g) Intends to be resident in Hanoi Capital for the next 12 months.
VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version For patients visiting emergency department (ED) with (a), (b) and (c) criteria, assessment of airflow limitation will be done after initial treatment at ED. If for any reason that a patient cannot do spirometry and peak flow meter, the follow-up at outpatient department within 14 days will be arranged.

Inclusion criteria for smoking cessation intervention for health workers
The health facility smoking cessation intervention is a facility-wide intervention.
Therefore, all HCWs in the facilities will be eligible to be included in the intervention.
HCWs who meet the following criteria are eligible for the SCP aiming to help them quit. Accordingly, there will be four groups of study participants. Figure 2 summarises the inclusion algorithm.
Group A: Current smokers who do not have airflow limitation. Patients in this group will be offered the patient smoking cessation intervention.
Group B: Patients with airflow limitation who do not smoke. Patients in this group will be offered the CRD intervention.
Group C: Current smokers who have airflow limitation. Patients in this group will be offered both the patient smoking cessation intervention and the CRD intervention.
VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version 18 Finally, Group D will be HCWs in the three district health facilities where the facility-wide smoking cessation program is conducted.

Exclusion criteria
(a) Patients who are unable to provide informed consent (b) Patients who are allergic to budesonide or formoterol will be excluded from the chronic respiratory disease intervention.
(c) Women who know they are pregnant will be excluded from the chronic respiratory disease intervention. The investigators will provide a training session regarding the three interventions before implementing them. The components included are listed in Table 4.

Interventions and follow-up
VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version 20

The chronic respiratory disease intervention
After excluding alternative causes of their respiratory symptoms, patients will be screened with spirometry or peak expiratory flow if spirometry cannot be performed (Table 1). Those who meet the inclusion criteria will be invited to participate in the chronic respiratory disease intervention. The chronic respiratory disease intervention will follow an algorithm that consists of the following elements: 1. Participant demographics, blood tests (full blood count including white blood cell count, eosinophil count), and fractional exhaled nitric oxide will be recorded by clinic staff in a record sheet designed for this study.  (Table 5). When a patient has an acute worsening of respiratory symptoms that requires a total dose of more than 6 inhalations of as-needed budesonide/formoterol a day over a period of 3 days, prednisolone 1mg/kg (no more than 40mg) should be added for 3-5 days.
4. In addition, if a patient reports purulent sputum (i.e. yellow or green colour and increased volume compared to normal) +/-fever of over 37. 7. Routine follow-up at clinics will be scheduled by staff at district facilities.
At these visits, the treating health workers will discuss the following with patients: • symptom control • need to step up according to the algorithm • need for use of oral steroids (see Table 5) • assessment and treatment changes 8. Unscheduled follow-up will occur if patients have symptoms that are not adequately controlled despite use of the 'step up' algorithm. At these visits, trained health workers will discuss the following with patients: • symptom control • need to step up according to the algorithm • need for use of oral steroids (see Table 5) 9. Assessment and treatment changes will be documented by district staff in the record sheet. 10. For patients at step 3 of the treatment algorithm (Figure 4), specialist care is necessary. These patients will be referred to Hanoi Lung Hospital for further clinical assessment and further treatment suggestions by a respiratory specialist at outpatient department.
11. For women who become pregnant during the study, they will consult their doctor to decide whether to continue treatment.
VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version 23

Definitions of poor symptom control and acute exacerbation
12. Definition for poor symptom control: a symptom control questionnaire (Table 6) derived from Asthma Control Test will be used for symptom control evaluation. A score of less than 20 will be considered poor symptom control. 13. Definition for acute exacerbation: an acute worsening of respiratory symptoms within days that requires oral steroid, as described in the exacerbation plan, or a hospital visit.

week follow-up visit
14. Patients will attend the clinic 4 weeks after their enrolment. 15. At this 4 week visit, a follow-up spirometry will be performed (before and after bronchodilator [salbutamol]). This will allow an assessment of the degree of bronchodilator reversibility. Patients who cannot perform spirometry will have peak flow meter (Table 1).

Follow-up
16. Patients will be followed by research staff for outcome evaluation at 4 weeks, 3 months, 6 months, 9 months, and 12 months after discharge from a district facility. The following outcomes will be recorded in a register book: • symptom control questionnaire score (Table 6), • mMRC Dyspnea Scale (Table 7), • CAAT score (Table 8), • hospital visits due to exacerbations, and • Self-reported adherence to recommended frequency of dosing.
VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version 24

The patient smoking cessation intervention and the health facility smoking cessation intervention
This study will apply four strategies to reduce smoking within the health facility and enhance patient smoking cessation. VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version 25 2. Delivery of brief smoking cessation advice by staff : HCWs will be trained to screen patients for smoking status, as indicated in Figure 1 and Figure 2, and offer brief counselling to patients with the 5As approach (Table 9) 17 .

Smoking cessation materials:
o Written material to help patients quit will also be offered to all patients

Integrated phone call and interactive two-way text message follow-up:
o See following section and Appendix 1 for the procedures.

Enrolment of smokers
• All patients attending the clinic will be asked about their current smoking status and will be documented.
• The proportion of patients receiving screening and counselling for smoking will be reported.
• Patients who agree to participate and provide consent will receive self-help material.

Follow-up of smokers
• Recruited patients with receive a phone call from research staff to provide smoking cessation counselling within 24 hours.
• They will then receive outpatient phone follow-up from a centralised call centre, by trained health workers, to support their cessation at:  • Urinary cotinine will be used for biochemical verification of smoking cessation at 12 months 19 .

Staff smoking cessation
• Staff who are identified as current smokers will be invited to participate.
They will receive the same follow-up, materials, and services indicated above. Staff counseling will be confidential, with the leadership of the district clinics not able to access the records of health workers involved in this program.

Outcomes
The findings of this study will be used to inform the implementation of the VCAPS RCT (the VCAPS 4 study). We will measure a number of clinical and process indicators for the three interventions.

Primary outcome of the chronic respiratory disease intervention:
The proportion of patients presenting with respiratory symptoms who have airflow limitation or probable asthma who have at least one exacerbation during the 12 months following enrolment At each follow-up for outcome evaluation (4 weeks, 3, 6, and 9 months) and the 12 month end-point review, the research staff will ask about acute exacerbations that will be used for calculating the proportion.

Secondary outcome of the CRD intervention:
The proportion of patients completing the 'cascade of care' for CRD management. The cascade of care refers to each step in the diagnostic and treatment pathway that is expected according to optimal clinical practice. This study will measure the progression through each of the following steps:

The proportion of patients presenting with chronic respiratory symptoms consistent with CRD
Among patients presenting with respiratory symptoms, how many of them have at least one prior episode of respiratory symptoms that has required VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version 27 attendance at a public or private health care facility or private pharmacy within the past two years OR score three or more in the respiratory symptom questionnaire.

The proportion of patients with chronic respiratory symptoms who initiate diagnostic assessment in health care facilities
How many patients among those in the previous step begin diagnostic evaluation, including spirometry (or peak flow meter if the patient cannot or is contraindicated to perform spirometry).

The proportion of patients who complete diagnostic assessment
How many patients among those in the previous step successfully complete a clinical assessment, and spirometry OR peak expiratory flow OR documented ineligibility for both spirometry and peak expiratory flow in the record sheet. Among patients prescribed with prn budesonide/formoterol, how many (a) return to the district facility to attend scheduled clinical evaluation at 4 weeks, and (b) have completed either spirometry OR peak flow meter OR are ineligible for spirometry at that visit.

The proportion of patients continuing recommended treatment 12 months after their initial presentation
Among patients who commence therapy, how many of them inform research staff that they continue to take the recommended therapy algorithm until the end-point review.

The proportion of current smokers with documentated brief counselling by health workers
Among current smokers, how many have the health workers documented they have provided brief advice.

The proportion of current smokers agreeing to enrol in the SCP
Among patients receiving counselling from the health workers, how many agree to enrol in the smoking cessation intervention The proportion of current smokers participating in the smoking cessation program VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version 29 who report no smoking in past 7 days at 4 weeks, 3, 6, 9 and 12 months.

Abstinence from smoking: health-care workers
The outcome measures described in 6.8.3 and 6.8.4 will also be measured for HCWs, and reported separately. Follow-up will be at the same time periods as for the patients.

Secondary outcomes shared by the interventions: Attitude and perceptions of patients and HCWs regarding the interventions
All participants will be asked to complete a quantitative survey at 3 months (either in-person or by phone call interview by research staff).

Secondary outcomes shared by the interventions: Qualitative interviews
A qualitative assessment will also be conducted at 3 months for a sample of up to 20 patients and healthcare providers receiving each of the interventions (i.e. a total of up to 20 interviews). A purposive sampling approach will be applied. The focus will be how to improve acceptance and scalability of the interventions.

ANALYTIC METHODS
In this study, we will calculate the proportion of patients participating in CRD intervention who have at least one exacerbation and proportion of participants joining smoking cessation intervention who quit smoking during the 12-month follow-up period. The proportions of population participating and following the procedures along the study process, namely the cascade of care, will also be obtained.
Inferential statistics will be used to identify risk factors for drop out during the cascade of care.
The results will be compared with data from existing literature. Reasons for drop-out and nonadherence will be analysed.
The abovementioned analysis, along with the qualitative assessment of attitude and perceptions regarding the two interventions, will be used to guide the design of the

KNOWLEDGE DISSEMINATION PLAN
The findings of this pilot study and the main study will be published in a peer reviewed international scientific journal. The findings will be provided in a Policy Brief to the Vietnam Ministry of Health, to contribute to future policy development.
The outcomes will also be presented at the annual scientific meeting of the Global Alliance for Chronic Diseases, in order to inform the application of this intervention in other low-and middle-income countries.

Appendix 1: Examples of text messages for smoking cessation intervention
The detailed procedure of text message service will be constructed based on literature 23,24 and be adopted to fit culture and local context in Vietnam. Listed here are some examples.

Timing of text message Content
On the designated quit date Today is the date! Today is the start of being quit forever. You can achieve it and we are here to help! In response to text "crave" We know it's difficult. However, cravings generally last less than 5 minutes. Let's try something to distract yourself! How about try sipping a drink slowly until the craving is over?
In response to text "lapse" Don't feel bad or guilty if you've smoked again. It is a normal part of the quitting process. Encourage yourself as you already stopped for a while. Keep going, don't give up! In response to text "call" It's OK to ask for help. Our staff will call you as soon as possible to help you! VCAPS-3 Study: An integrated public health strategy to manage chronic respiratory disease and reduce smoking in three district clinics in Vietnam: a prospective cohort study Protocol, Version 12.3, 21/04/2020, English version